Gonadotropins serve important functions in a variety of bodily functions including metabolism, temperature regulation and the reproductive process. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. The pituitary gonadotropin FSH (follicle stimulating hormone) for example plays a pivotal role in the stimulation of follicle development and maturation whereas LH (luteinizing hormone) induces ovulation (Sharp, R. M. Clin Endocrinol. 33:787-807, 1990; Dorrington and Armstrong, Recent Prog. Horm. Res. 35:301-342, 1979). Currently, FSH is applied clinically for ovarian stimulation i.e. ovarian hyperstimulation for in vitro fertilisation (IVF) and induction of ovulation in infertile anovulatory women (Insler, V., Int. J. Fertility 33:85-97, 1988, Navot and Rosenwaks, J. Vitro Fert. Embryo Transfer 5:3-13, 1988), as well as for male hypogonadism and male infertility.
The gonadotropin FSH is released from the anterior pituitary under the influence of gonadotropin-releasing hormone and estrogens, and from the placenta during pregnancy. In the female, FSH acts on the ovaries promoting development of follicles and is the major hormone regulating secretion of estrogens. In the male, FSH is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis. Purified FSH is used clinically to treat infertility in females and for some types of failure of spermatogenesis in males. Gonadotropins destined for therapeutic purposes can be isolated from human urine sources and are of low purity (Morse et al, Amer. J. Reproduct. Immunol. and Microbiology 17:143, 1988). Alternatively, they can be prepared as recombinant gonadotropins. Recombinant human FSH is available commercially and is being used in assisted reproduction (Olijve et al. Mol. Hum. Reprod. 2:371, 1996; Devroey et al. Lancet 339:1170, 1992). The actions of the FSH hormone are mediated by a specific plasma membrane receptor that is a member of the large family of G-protein coupled receptors. These receptors consist of a single polypeptide with seven transmembrane domains and are able to interact with the Gs protein, leading to the activation of adenylate cyclase.
The FSH receptor is a highly specific target in the ovarian follicle growth process and is exclusively expressed in the ovary. Blocking of the receptor or inhibiting the signalling which is normally induced after FSH-mediated receptor activation will disturb follicle development and thus ovulation and fertility. Low molecular weight FSH antagonists could form the basis for new contraceptives, while low molecular weight FSH agonists can be used for the same clinical purposes as native FSH, i.e. for the treatment of infertility and for ovarian hyperstimulation on behalf of in vitro fertilisation.
Low molecular weight FSH mimetics with agonistic properties were disclosed in the International Application WO 2000/08015 (Applied Research Systems ARS Holding N.V.) and in WO 2002/09706 (Affymax Research Institute).
Certain tetrahydroquinoline derivatives have recently been disclosed in the International Application WO 2003/004028 (AKZO NOBEL N.V.) as FSH modulating substances, either having agonistic or antagonistic properties.
There remains a need for low molecular weight hormone mimetics that selectively activate the FSH receptor.
To that aim the present invention provides 2-methyl-4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives of general formula I
whereinR1 is (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl;R2 is halogen;R3 is SO2NR5R6 or (1-4C)alkoxy, optionally substituted with one of more fluorine atoms;X is O or NR7;R4 is R8-(2-8C)alkyl, R8-(3-8C)alkenyl, R8-(3-8C)alkynyl or R8-(2-4C)alkoxy(2-4C)-alkyl;Z is CN or NO2;R5 and R6 are independently H or (1-4C)alkyl; orR5 together with R6 and the N to which they are bonded form a 3-8 membered saturated ring optionally containing a further heteroatom selected from O and S;R8 is OH, (1-4C)alkoxy, NH2; NR9C(O)R11, NR9SO2R11 or C(O)NR9R10;R7 and R9 are independently H or (1-4C)alkyl;R10 is (1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, or phenyl(1-4C)alkyl or(2-5C)heteroaryl(1-4C)alkyl, both optionally substituted on the (hetero)aromatic ring with one or more substituents selected from OH, NH2, halogen, NO2, CF3, CN, (1-4C)-alkyl, (1-4C)alkoxy and (di)(1-4C)alkylamino;R11 is (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy(1-4C)alkyl, (3-6C)-cycloalkyl, (1-4C)alkoxy, (di)(1-4C)alkylamino, or phenyl or (2-5C)heteroaryl, both optionally substituted on the (hetero)aromatic ring with one or more substituents selected from OH, NH2, halogen, NO2, CF3, CN, (1-4C)alkyl, (1-4C)alkoxy and (di)(1-4C)alkylamino; or a pharmaceutically acceptable salt thereof.